Although we are at the end of the Congressionally-declared Decade for Pain Control and Research, chronic pain continues to be a leading public health epidemic, affecting more than 50 million Americans and costing more than $165 billion per year in treatment expenses and lost work productivity. Of particular note are those patients with chronic diseases, such as cancer and HIV, who suffer from treatment-related pain that cannot be controlled with conventional analgesics. Treatment-related pain affects approximately 50% of these patients, depending on drug and dosing regimen, which translates into nearly 700,000 Americans per year. The predominant symptom is excruciating unremitting pain that is resistant to traditional pharmacological treatments. As therapeutics become increasingly aggressive and diseases become chronic, this becomes a risk/benefit issue; patients must choose between increased life expectancies and constant suffering with decreased quality of life. This decision is untenable, and thus, the crucial question that must be answered is how to prevent or reverse persistent disease treatment-related pain. Recent mechanistic studies have found that the development and persistence of neuropathic pain stems in part from central sensitization in the spinal dorsal horn. Much like memory formation in the hippocampus, central sensitization in the spinal cord produces pain hypersensitivity that is uncoupled from noxious input. More simply put, innocuous inputs produce long lasting pain hypersensitivity. Recently, we made the preliminary discovery that antiretroviral treatment produces up-regulation of Brain-derived Neurotrophic Factor (BDNF) in the mouse spinal dorsal horn, causing central sensitization (hyperexcitability of spinal dorsal horn neurons) and the development and persistence of nocifensive (pain) behavior. Reducing levels of BDNF expression in vivo reversed this phenotype. These data implicating BDNF in treatment-related pain suggest that BDNF may represent a new target for drug development. However, further studies to determine precisely how chemotherapeutic drugs alter BDNF expression and that of the BDNF receptor, tyrosine kinase receptor B (trkB) are crucial first steps. One likely possibility is via epigenetic regulation of BDNF and trkB gene expression. In support of this idea, we have shown that alterations in DNA methylation and histone modifications in promoter regions produce changes in BDNF gene expression that regulate the capacity for long-term memory formation. Thus, we hypothesize that complex epigenetic regulation of BDNF and trkB may produce gene dysregulation that is mechanistically linked to long-term chemotherapy-induced neuropathic pain. In addition, we posit that other genes, not previously linked with nociception, may undergo epigenetic regulation and we will examine this question using chromatin immunoprecipitation (ChIP) followed by high-throughput next generation sequencing (ChIP-seq). Results from these studies will have broad impact beyond treatment-related pain to improve our understanding of chronic pain persistence and the role for epigenetic modifications.